Journal of Alzheimer's Disease - Volume 89, issue 4

Authors: Zawar, Ifrah | Mattos, Meghan K. | Manning, Carol | Quigg, Mark

Article Type: Research Article

Abstract: Background: While sleep disturbances appear to be risk factors in Alzheimer’s disease (AD) progression, information such as the prevalence across dementia severity and the influence on the trajectory of cognitive decline is unclear. Objective: We evaluate the hypotheses that the prevalence of insomnia differs by cognitive impairment, that sleep disturbances track with AD biomarkers, and that longitudinal changes in sleep disorders affect cognition. Methods: We used the National Alzheimer’s Coordinating Center Database to determine the prevalence of clinician-identified insomnia and nighttime behaviors in normal, mild cognitive impairment (MCI), and demented individuals. We evaluated mean Montreal Cognitive …Assessment (MoCA) scores, hippocampal volumes (HV), and CSF phosphorylated tau:amyloid-β ratios at first visit using analysis of variance with age as a covariate. In longitudinal evaluations, we assessed changes in MoCA scores and HV in insomnia and nighttime behaviors between the first and last visits. Results: Prevalence of insomnia was 14%, 16%, and 11% for normal, MCI, and dementia groups. Prevalence of nighttime behaviors was 14%, 21%, and 29% respectively. Insomnia patients had higher MoCA scores, larger HV, and lower pTauBeta than individuals without insomnia, indicating less neurodegeneration. In contrast, nighttime behaviors were associated with worse cognition, smaller HV, and higher pTauBeta. Similar findings were seen between longitudinal associations of sleep disorders and cognition and HV. Conclusion: Our findings suggest that insomnia is unreliably recognized in patients with cognitive impairment. Nighttime behaviors may better indicate the presence of sleep disturbances and have diagnostic specificity in AD over insomnia. Show more

Keywords: Dementia, hippocampus, insomnia, sleep, sleep insufficiency

DOI: 10.3233/JAD-220664

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1367-1374, 2022

Authors: Perales-Puchalt, Jaime | Townley, Ryan | Niedens, Michelle | Vidoni, Eric D. | Greiner, K. Allen | Zufer, Tahira | Schwasinger-Schmidt, Tiffany | McGee, Jerrihlyn L. | Arreaza, Hector | Burns, Jeffrey M.

Article Type: Research Article

Abstract: Background: Optimal care can improve lives of families with dementia but remains under-implemented. Most healthcare professional training is in person, time-intensive, and does not focus on key aspects such as early detection, and cultural competency. Objective: We explored the acceptability and preliminary effectiveness of a training, The Dementia Update Course, which addressed these issues. We hypothesized that the training would lead to increased levels of perceived dementia care competency among key healthcare workers, namely primary care providers (PCPs) and health navigators (HNs). Methods: We conducted pre-post training assessments among 22 PCPs and 32 HNs. The 6.5-h …training was remote, and included didactic lectures, case discussion techniques, and materials on dementia detection and care. Outcomes included two 5-point Likert scales on acceptability, eleven on perceived dementia care competency, and the three subscales of the General Practitioners Confidence and Attitude Scale for Dementia. We used paired samples t -tests to assess the mean differences in all preliminary effectiveness outcomes. Results: The training included 28.6% of PCPs and 15.6% of HNs that self-identified as non-White or Latino and 45.5% of PCPs and 21.9% of HNs who served in rural areas. PCPs (84.2%) and HNs (91.7%) reported a high likelihood to recommend the training and high satisfaction. Most preliminary effectiveness outcomes analyzed among PCPs (11/14) and all among HNs (8/8) experienced an improvement from pre- to post-training (p  < 0.05). Conclusion: A relatively brief, remote, and inclusive dementia training was associated with high levels of acceptability and improvements in perceived dementia care competency among PCPs and HNs. Show more

Keywords: Attitude of health personnel, dementia, education, healthcare professionals

DOI: 10.3233/JAD-220235

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1375-1384, 2022

Authors: Weible, Aldis P. | Wehr, Michael

Article Type: Research Article

Abstract: Background: Effective treatment of Alzheimer’s disease (AD) will hinge on early detection. This has led to the search for early biomarkers that use non-invasive testing. One possible early biomarker is auditory temporal processing deficits, which reflect central auditory pathway dysfunction and precede cognitive and memory declines in AD. Gap detection is a measure of auditory temporal processing, is impaired in human AD, and is also impaired in the 5XFAD mouse model of AD. Gap detection deficits appear as early as postnatal day 60 in 5XFAD mice, months before cognitive deficits or cell death, supporting gap detection as an early biomarker. …However, it remains unclear how gap detection deficits relate to the progression of amyloid pathology in the auditory system. Objective: To determine the progression of amyloid pathology throughout the central auditory system and across age in 5XFAD mice. Methods: We quantified intracellular and extracellular antibody labelling of Aβ42 in 6 regions of the central auditory system from p14 to p150. Results: Pathology appeared first in primary auditory cortex (A1) as intracellular accumulation of Aβ42 in layer 5 pyramidal neurons by age p21. Extracellular plaques appeared later, by age p90, in A1, medial geniculate body, and inferior colliculus. Auditory brainstem structures showed minimal amyloid pathology. We also observed pathology in the caudal pontine reticular nucleus, a brainstem structure that is outside of the central auditory pathway but which is involved in the acoustic startle reflex. Conclusion: These results suggest that Aβ42 accumulation, but not plaques, may impair gap detection. Show more

Keywords: Aβ42, Alzheimer’s disease, biomarker, gap detection, inferior colliculus, medial geniculate body, primary auditory cortex

DOI: 10.3233/JAD-220538

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1385-1402, 2022

Authors: Nyholm, Ebba | Torkpoor, Rozita | Frölich, Kristin | Londos, Elisabet | Cicognola, Claudia

Article Type: Research Article

Abstract: Background: People with a migration background are underrepresented in dementia research and disfavored in assessment and treatment, and many foreign-born individuals with dementia remain undiagnosed. Objective: The aim of this study was to examine whether there is inequality in the clinical assessment of dementia between native and foreign-born individuals in Sweden. Methods: Information was gathered retrospectively from a cohort of 91 native and 36 foreign-born patients attending four memory clinics in Skåne, Sweden. Data included information on cognitive test results, cerebrospinal fluid biomarkers, scores at structural imaging scales of global cortical atrophy (GCA), medial temporal lobe …atrophy (MTA) and the Fazekas scale, laboratory measures of thyroid-stimulating hormone, calcium, albumin, homocysteine, hemoglobin, cobalamin (vitamin B12), and folate (vitamin B9), contact with health care, and treatment. Results: Foreign-born patients had lower educational level and scored lower on Mini-Mental State Examination and Clock Drawing Test (p  < 0.001–0.011). Relatives initiated contact with health care to a higher extent in the foreign-born group (p  = 0.031). Foreign-born patients had less white matter lesions (p  = 0.018). Additionally, Alzheimer’s disease (AD) biomarkers were significantly less used in foreign-born patients to support an AD diagnosis (p  = 0.001). No significant differences were found for scores on GCA and MTA, laboratory measures, or initiated treatment. Conclusion: Although native and foreign-born patients were predominantly homogenous regarding examined variables, differences in the diagnostic process and underlying biological correlates of dementia exist and need to be further investigated in a larger sample. Show more

Keywords: Alzheimer’s disease, cognitive impairment, dementia, health care inequalities, immigrants

DOI: 10.3233/JAD-220177

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1403-1412, 2022

Authors: Ohno, Kazuya | Abdelhamid, Mona | Zhou, Chunyu | Jung, Cha-Gyun | Michikawa, Makoto

Article Type: Research Article

Abstract: Background: We previously reported the effects of a probiotic strain, Bifidobacterium breve MCC1274, in improving cognitive function in preclinical and clinical studies. Recently, we demonstrated that supplementation of this strain led to decreased amyloid-β production, attenuated microglial activation, and suppressed inflammation reaction in the brain of APP knock-in (App NL  - G  - F ) mice. Objective: In this study, we investigated the plasma metabolites to reveal the mechanism of action of this probiotic strain in this Alzheimer’s disease (AD)-like model. Methods: Three-month-old mice were orally supplemented with B. breve MCC1274 or saline for four …months and their plasma metabolites were comprehensively analyzed using CE-FTMS and LC-TOFMS. Results: Principal component analysis showed a significant difference in the plasma metabolites between the probiotic and control groups (PERMANOVA, p  = 0.03). The levels of soy isoflavones (e.g., genistein) and indole derivatives of tryptophan (e.g., 5-methoxyindoleacetic acid), metabolites with potent anti-oxidative activities were significantly increased in the probiotic group. Moreover, there were increased levels of glutathione-related metabolites (e.g., glutathione (GSSG)_divalent, ophthalmic acid) and TCA cycle-related metabolites (e.g., 2-Oxoglutaric acid, succinic acid levels) in the probiotic group. Similar alternations were observed in the wild-type mice by the probiotic supplementation. Conclusion: These results suggest that the supplementation of B. breve MCC1274 enhanced the bioavailability of potential anti-oxidative metabolites from the gut and addressed critical gaps in our understanding of the gut-brain axis underlying the mechanisms of the probiotic action of this strain in the improvement of cognitive function. Show more

Keywords: Alzheimer’s disease, anti-oxidative activity, Bifidobacterium breve MCC1274, glutathione, soy isoflavones, TCA cycle, tryptophan derivative

DOI: 10.3233/JAD-220479

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1413-1425, 2022

Authors: Comon, Martin | Rouch, Isabelle | Edjolo, Arlette | Padovan, Catherine | Krolak-Salmon, Pierre | Dorey, Jean-Michel

Article Type: Research Article

Abstract: Background: Facial emotion recognition (FER) and gaze direction (GD) identification are core components of social cognition, possibly impaired in many psychiatric or neurological conditions. Regarding Alzheimer’s disease (AD), current knowledge is controversial. Objective: The aim of this study was to explore FER and GD identification in mild AD compared to healthy controls. Methods: 180 participants with mild AD drawn from the PACO study and 74 healthy elderly controls were enrolled. Participants were asked to complete three socio-cognitive tasks: face sex identification, recognition of facial emotions (fear, happiness, anger, disgust) expressed at different intensities, and GD discrimination. …Multivariate analyses were conducted to compare AD participants and healthy controls. Results: Sex recognition was preserved. GD determination for subtle deviations was impaired in AD. Recognition of prototypically expressed facial emotions was preserved while recognition of degraded facial emotions was impacted in AD participants compared to controls. Use of multivariate analysis suggested significant alteration of low-expressed fear and disgust recognition in the AD group. Conclusion: Our results showed emotion recognition and GD identification in patients with early-stage AD compared to elderly controls. These impairments could be the object of specific therapeutic interventions such as social cognition remediation or raising awareness of primary caregivers to improve the quality of life of patients with early AD. Show more

Keywords: Alzheimer’s disease, elderly, facial emotion recognition, social cognition

DOI: 10.3233/JAD-220401

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1427-1437, 2022

Authors: de Oliveira Otto, Marcia C. | Li, Xinmin S. | Wang, Zeneng | Siscovick, David S. | Newman, Anne B. | Lai, Heidi Tsz Mung | Nemet, Ina | Lee, Yujin | Wang, Meng | Fretts, Amanda | Lemaitre, Rozenn N. | Tang, W.H. Wilson | Lopez, Oscar | Hazen, Stanley L. | Mozaffarian, Dariush

Article Type: Research Article

Abstract: Background: Animal studies suggest that gut microbiome metabolites such as trimethylamine N-oxide (TMAO) may influence cognitive function and dementia risk. However potential health effects of TMAO and related metabolites remain unclear. Objective: We examined prospective associations of TMAO, γ -butyrobetaine, crotonobetaine, carnitine, choline, and betaine with risk of cognitive impairment and dementia among older adults aged 65 years and older in the Cardiovascular Health Study (CHS). Methods: TMAO and metabolites were measured in stored plasma specimens collected at baseline. Incident cognitive impairment was assessed using the 100-point Modified Mini-Mental State Examination administered serially up to 7 …times. Clinical dementia was identified using neuropsychological tests adjudicated by CHS Cognition Study investigators, and by ICD-9 codes from linked Medicare data. Associations of each metabolite with cognitive outcomes were assessed using Cox proportional hazards models. Results: Over a median of 13 years of follow-up, 529 cases of cognitive impairment, and 522 of dementia were identified. After multivariable adjustment for relevant risk factors, no associations were seen with TMAO, carnitine, choline, or betaine. In contrast, higher crotonobetaine was associated with 20–32% higher risk of cognitive impairment and dementia per interquintile range (IQR), while γ -butyrobetaine was associated with ∼25% lower risk of the same cognitive outcomes per IQR.∥ Conclusion: These findings suggest that γ -butyrobetaine, crotonobetaine, two gut microbe and host metabolites, are associated with risk of cognitive impairment and dementia. Our results indicate a need for mechanistic studies evaluating potential effects of these metabolites, and their interconversion on brain health, especially later in life. Show more

Keywords: Aging, cognition, dementia, diet, gut metabolites

DOI: 10.3233/JAD-220477

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1439-1452, 2022

Authors: Gong, Xianmin | Shi, Lin | Wu, Yuanyuan | Luo, Yishan | Kwok, Timothy

Article Type: Research Article

Abstract: Background: The effects of B vitamins on mild cognitive impairment (MCI) patients’ cognition have been mixed, suggesting the existence of moderating factors. Objective: A post hoc analysis of a negative B vitamin trial was performed to examine the potential modulating effect of regional brain atrophy on the cognitive response to B vitamins in MCI patients. Methods: In the 24-month randomized trial, 279 MCI outpatients took 500μ #x03BC;g methylcobalamin and 400μ #x03BC;g folic acid once per day or placebo tablets once per day. Sixty-four aspirin users were excluded from analysis as aspirin use has been found …to have significant negative interaction effects. Subjects were followed up at months 12 and 24. The primary cognitive outcome was clinical dementia rating scale sum of boxes (CDR_SOB). In a subgroup of 83 subjects, MRI brain scans were performed at baseline to estimate regional brain atrophy ratios. Results: Among the trial subjects who had MRI data, B vitamin supplementation had no significant effect on CDR_SOB, despite having significant homocysteine lowering effects. The atrophy ratio of the left frontal lobe significantly moderated the effect of B vitamin supplementation on CDR_SOB, after adjusting for confounders, in that B vitamin supplementation was associated with lower CDR_SOB scores (i.e., better cognitive function) at the 24th month among those patients with above median atrophy ratios, but not among those with lower atrophy ratios, in the left frontal lobe. Conclusion: B vitamins may be more effective in slowing down cognitive decline in MCI patients with atrophy in the left frontal lobe. Show more

Keywords: B vitamins, brain atrophy, folate, homocysteine, mild cognitive impairment Clinical trial registration: Centre for Clinical Research and Biostatistics (CCRB) Clinical Trials Registry: CUHK_CCT00373

DOI: 10.3233/JAD-220685

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1453-1461, 2022

Authors: Jaakkimainen, Liisa | Duchen, Raquel | Lix, Lisa | Al-Azazi, Saeed | Yu, Bing | Butt, Debra | Park, Su-Bin | Widdifield, Jessica

Article Type: Research Article

Abstract: Background: Early onset dementia (EOD) occurs when symptoms of dementia begin between 45 to 64 years of age. Objective: We developed and validated health administrative data algorithms for EOD and compared demographic characteristics and presence of comorbid conditions amongst adults with EOD, late onset dementia (LOD) and adults with no dementia in Ontario, Canada. Methods: Patients aged 45 to 64 years identified as having EOD in their primary care electronic medical records had their records linked to provincial health administrative data. We compared several combinations of physician’s claims, hospitalizations, emergency department visits and prescriptions. Age-standardized incidence …and prevalence rates of EOD were estimated from 1996 to 2016. Results: The prevalence of EOD for adults aged 45 to 64 years in our primary care reference cohort was 0.12%. An algorithm of ≥1 hospitalization or ≥3 physician claims at least 30 days apart in a two-year period or ≥1 dementia medication had a sensitivity of 72.9% (64.5–81.3), specificity of 99.7% (99.7–99.8), positive predictive value (PPV) of 23.7% (19.1–28.3), and negative predictive value of 100.0%. Multivariate logistic regression found adults with EOD had increased odds ratios for several health conditions compared to LOD and no dementia populations. From 1996 to 2016, the age-adjusted incidence rate increased slightly (0.055 to 0.061 per 100 population) and the age-adjusted prevalence rate increased three-fold (0.11 to 0.32 per 100 population). Conclusion: While we developed a health administrative data algorithm for EOD with a reasonable sensitivity, its low PPV limits its ability to be used for population surveillance. Show more

Keywords: Administrative data, algorithm, early onset dementia, primary care electronic medical records

DOI: 10.3233/JAD-220384

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1463-1472, 2022

Authors: Hsu, Chun Liang | Falck, Ryan S. | Backhouse, Daniel | Chan, Patrick | Dao, Elizabeth | ten Brinke, Lisanne F. | Manor, Brad | Liu-Ambrose, Teresa

Article Type: Research Article

Abstract: Background: Poor sleep quality is common among older individuals with mild cognitive impairment (MCI) and may be a consequence of functional alterations in the brain; yet few studies have investigated the underlying neural correlates of actigraphy-measured sleep quality in this cohort. Objective: The objective of this study was to examine the relationship between brain networks and sleep quality measured by actigraphy. Methods: In this cross-sectional analysis, sleep efficiency and sleep fragmentation were estimated using Motionwatch8 (MW8) over a period of 14 days in 36 community-dwelling older adults with possible MCI aged 65–85 years. All 36 participants …underwent resting-state functional magnetic resonance imaging (fMRI) scanning. Independent associations between network connectivity and MW8 measures of sleep quality were determined using general linear modeling via FSL. Networks examined included the somatosensory network (SMN), frontoparietal network (FPN), and default mode network (DMN). Results: Across the 36 participants (mean age 71.8 years; SD = 5.2 years), mean Montreal Cognitive Assessment score was 22.5 (SD = 2.7) and Mini-Mental State Examination score was 28.3 (SD = 1.5). Mean sleep efficiency and fragmentation index was 80.1% (SD = 10.0) and 31.8 (SD = 10.4) respectively. Higher sleep fragmentation was significantly correlated with increased connectivity between the SMN and insula, the SMN and posterior cingulate, as well as FPN and primary motor area (FDR-corrected, p  < 0.004). Conclusion: Functional connectivity between brain regions involved in attentional and somatosensory processes may be associated with disrupted sleep in older adults with MCI. Show more

Keywords: Mild cognitive impairment, objective sleep quality, older adults, resting-state functional magnetic resonance imaging

DOI: 10.3233/JAD-220457

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1473-1482, 2022

Authors: Wright, Joy R. | Deen, Quazi Fahm E. | Stevenson, Anna | Telford-Cooke, Leolie L. | Parker, Craig | Martin-Ruiz, Carmen | Steinert, Joern R. | Kalaria, Raj N. | Mukaetova-Ladinska, Elizabeta B.

Article Type: Research Article

Abstract: Background: Myeloperoxidase (MPO), a neutrophil-derived pro-inflammatory protein, co-localizes with amyloid-β (Aβ) plaques in Alzheimer’s disease (AD). Anti-dementia treatment may facilitate efflux of Aβ and associated plaque proteins from the brain to the peripheral circulation, therefore providing potential biomarkers for the monitoring of donor response to drug treatment. Objective: We investigated the diagnostic utility of MPO as a biomarker of AD, and how anti-dementia treatment alters plasma MPO concentration. Methods: Thirty-two AD patients were recruited, and plasma collected pre-drug administration (baseline), and 1- and 6-months post-treatment. All patients received cholinesterase inhibitors (ChEIs). At baseline and 6 months, …patients underwent neuropsychological assessment. Forty-nine elderly healthy individuals with normal cognitive status served as controls. Plasma MPO concentration was measured by ELISA. Results: AD drug naïve patients had similar plasma MPO concentration to their control counterparts (p  > 0.05). Baseline MPO levels positively correlated with Neuropsychiatric Inventory score (r  = 0.5080; p  = 0.011) and carer distress (r  = 0.5022; p  = 0.012). Following 1-month ChEI treatment, 84.4% of AD patients exhibited increased plasma MPO levels (p  < 0.001), which decreased at 6 months (p  < 0.001). MPO concentration at 1 month was greatest in AD patients whose memory deteriorated during the study period (p  = 0.028), and for AD patients with deterioration in Cornell assessment score (p  = 0.044). Conclusion: Whereas baseline MPO levels did not differentiate between healthy and AD populations, baseline MPO positively correlated with initial Neuropsychiatric Inventory evaluation. Post-treatment, transient MPO upregulation in ChEI-treated patients may reflect worse therapeutic outcome. Further studies are required to assess the potential of plasma MPO as an AD therapeutic biomarker. Show more

Keywords: Alzheimer’s disease, biomarkers, cholinesterase inhibitors, inflammation, myeloperoxidase, plasma

DOI: 10.3233/JAD-220642

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1483-1492, 2022

Authors: Beheshti, Iman | Geddert, Natasha | Perron, Jarrad | Gupta, Vinay | Albensi, Benedict C. | Ko, Ji Hyun

Article Type: Research Article

Abstract: Background: We previously introduced a machine learning-based Alzheimer’s Disease Designation (MAD) framework for identifying AD-related metabolic patterns among neurodegenerative subjects. Objective: We sought to assess the efficiency of our MAD framework for tracing the longitudinal brain metabolic changes in the prodromal stage of AD. Methods: MAD produces subject scores using five different machine-learning algorithms, which include a general linear model (GLM), two different approaches of scaled subprofile modeling, and two different approaches of a support vector machine. We used our pre-trained MAD framework, which was trained based on metabolic brain features of 94 patients with AD …and 111 age-matched cognitively healthy (CH) individuals. The MAD framework was applied on longitudinal independent test sets including 54 CHs, 51 stable mild cognitive impairment (sMCI), and 39 prodromal AD (pAD) patients at the time of the clinical diagnosis of AD, and two years prior. Results: The GLM showed excellent performance with area under curve (AUC) of 0.96 in distinguishing sMCI from pAD patients at two years prior to the time of the clinical diagnosis of AD while other methods showed moderate performance (AUC: 0.7–0.8). Significant annual increment of MAD scores were identified using all five algorithms in pAD especially when it got closer to the time of diagnosis (p  < 0.001), but not in sMCI. The increased MAD scores were also significantly associated with cognitive decline measured by Mini-Mental State Examination in pAD (q  < 0.01). Conclusion: These results suggest that MAD may be a relevant tool for monitoring disease progression in the prodromal stage of AD. Show more

Keywords: Alzheimer’s disease, brain metabolism, FDG PET, machine learning

DOI: 10.3233/JAD-220585

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1493-1502, 2022

Authors: George, Daniel R.

Article Type: Book Review

DOI: 10.3233/JAD-220791

Citation: Journal of Alzheimer's Disease, vol. 89, no. 4, pp. 1503-1505, 2022